Treatment of angina pectoris with a long-acting vasodilating agent and a beta adrenergic receptor blocking agent

ABSTRACT

A pharmacologic preparation is disclosed for the treatment of angina pectoris consisting of a mixture of a long-acting vasodilating agent such as pentaerythritol tetranitrate, erythrityl tetranitrate or isosorbide dinitrate and a beta adrenergic receptor blocking agent such as 1-(3,4dichlorophenyl)-2-isopropylamino-1-ethanol, 1-(3,4-dihydrophenyl2-isopropylamino-1-ethanol, 1-(2,5-dimethoxyphenyl)-2-methyl-2-tbutylamino-1-ethanol, 1-3,4-dichlorophenyl)-2-methyl-2isopropylamino-1-ethanol, 1-(4-methanesulphonylaminophenyl)-2isopropylamino-1-ethanol, 1-(3-tolyloxy)-3-isopropylamino-2propanol, 1-(5,6,7,8-tetrahydronaphth-2-yl)-2-s-butylamino-1ethanol, 1-(2-allylphenoxy)-3-isopropylamino-2-propanol, 1-(pnitrophenyl)-2-isopropylamino-1-ethanol, 1-(p-nitrophenyl)-2-nbutylamino-1-ethanol or 1-(isopropylamino)-3-(1-naphthyloxy)-2propanol hydrochloride. The vasodilating agent and the beta blocking agent can be administered together or separately at short intervals such that the therapeutic actions of the two drugs overlap.

United States Patent i191 Russek [11] 3,832,470 51' Aug. 27, 1974 TREATMENT OF ANGINA PECTORIS WITH A LONG-ACTING VASODHJATING AGENT AND A BETA ADRENERGIC RECEPTOR BLOCKING AGENT [76] Inventor: Henry Irving Russek, 176 Hart Blvd., Staten Island, NY. 10301 [22] Filed: Oct. 6, 1969 21 Appl. No.: 866,098

Related US. Application Data [63] Continuation of Ser, No. 701,079, Jan. 29, 1968.

[52] US. Cl 424/330, 424/285, 424/349 [51] Int. Cl A6lk 27/00 [58] Field of Search 424/285, 330, 349

[56] References Cited UNITED STATES PATENTS 3,275,654 9/1966 Wilhelm et a1. 424/285 3,328,424 6/1967 Schenker et al..... 424/330 3,379,761 4/1968 Wilhelm 424/330 3,483,221 12/1969 Wilhelm et al. 424/285 OTHER PUBLICATIONS Epstein et al., The New England Journal of Medicine, Vol. 275, No. 20, pages 1106-1112, Nov. 1966. Physicians Desk Reference, 19th ed., published by Medical Economics, lnc., Oradell, N.J., pages 570, 577 and 647, 1964.

Primary ExaminerRichard L. Huff Attorney, Agent, or FirmMcLean, Boustead & Sayre l ABSTRACT ethanol, l-(4-methanesulphonylaminophenyl)-2- isopropylamino- 1 -ethanol, 1 3-toly1oxy)-3 isopropylamino-2-propanol, 1-(5,6,7,8-

tetrahydronaphth-Z-yl )-2-s-buty1amino- 1 -ethanol, 1

(2-allylphenoxy)-3-isopropylamino-2-propanol, l-(pv nitrophenyl )-2-isopropylamino- 1 -ethanol, 1 pnitrophenyl )-2-n-butylamino- 1 -ethanol or 1 (isopropylamino)-3-( 1-naphthyloxy)-2-propanol hydrochloride. The vasodilating agent and the beta blocking agent can be administered together or separately at short intervals such that the therapeutic actions of the two drugs overlap.

1 Claim, N0 Drawings TREATMENT OF ANGINA PECTORIS WITH A LONG-ACTING VASODILATING AGENTAND A BETA ADRENERGIC RECEPTOR BLOCKING AGENT BACKGROUND OF THE INVENTION its effects usually disappear in less than a half hour and its use has therefore been generally restricted to administration at the time of an actual or anticipated anginal attack. Longer acting nitrates such as pentaerythritol tetranitrate, erythrityl tetranitrate and isosorbide dinitrate have been suggested which afford relief over greater periods up to four hours or more and are therefore useful in prophylactic therapy to increase a patients tolerance to exercise and to decrease the number and severity of anginal attacks. The relief afforded by these longer acting nitrates, however, is a moderate form of relief which in most instances and especially in cases of severely diseased patients is far short of the degree of relief toward which the treatment is directed. While they improve a patients exercise tolerance, the improvement is often moderate and abnormal electrocardiographic responses can still occur after a relatively short exercise.

In addition to the nitrates which act as vasodilating agents other substances have been suggested for the treatment of angina pectoris. Among these are the beta adrenergic receptor blocking agents, such as l-(3,4- dichlorophenyl )-2-isopropylamino- 1 -ethanol, l-( 3,4- dihydrophenyl-2-isopropylaminol-ethanol, l-( 2,5- dimethoxyphenyl)-2-methyl-2-t-butylamino-l-ethanol, l-( 3 ,4-dichlorophenyl )-2-methyl-2-isopropylaminol ethanol, l-( 4-methanesulphonylaminophenyl )-2- isopropylamino-ethanol, l-(3-tolyloxy)-3- isopropylamino-2-propanol, l-(5,6,7,8- tetrahydronaphth-Z-yl)-2-s-butylaminoethanol, l-(2- allylphenoxy)-3-isopropylamino-2-propanol, l-(pnitrophenyl)-2-isopropylaminoethanol, l-(pnitrophenyl )-2-n-butylaminoethanol and l- (isopropylamino)-3-( l-naphthyloxy)-2-propanol hydrochloride, which tend to decrease the work of the heart. These have provided relief to about the same extent as that provided by the vasodilating agents and are therefore helpful in the treatment of angina pectoris but fail to provide the degree of relief desired. The level of relief provided by both the vasodilating nitrates and the beta blocking agents is limited by the dosages to which the patients can be safely subjected and therefore the quantum of relief noted above cannot be increased by merely increasing the amount of the drug administered as to do so would exceed the tolerance level which in the case of the nitrates typically causes headache, weakness, faintness, or shock.

It has also been suggested to increase the efficacy of anti-angina] agents by the combination of the agent with other drugs, e.g., a tranquilizing agent. The applicability of these combinations, however, is limited to those instances in which the angina! attack is precipitated by non-coronary disorders or irregularitiesupon which the second drug is effective.

SUMMARY OF INVENTION It has now been found that a certain novel combination of the previously known anti-anginal compositions provides a degree of relief not heretofore obtainable and that patients treated with this new combination exhibit vastly improved exercise tolerances and exercise-electrocardiographic responses.

The present invention, therefore, provides pharmacologic compositions and a method for the treatment of angina pectoris. The pharmacologic compositions of my invention are a mixture of a long-acting vasodilating agent and a beta adrenergic receptor blocking agent. The method of my invention involves the administration to a patient suffering from angina pectoris of a vasodilating agent and a beta adrenergic receptor blocking agent either together or at relatively short intervals such that the therapeutic actions of the two drugs overlap.

The principal vasodilating agents suitable for use in the compositions and method of this invention are the long-acting nitrates, pentaerythritol tetranitrate, erythrityl tetranitrate, and isosorbide dinitrate. While I have found that the above vasodilators such as isosorbide dinitrate give especially good results in the practice of my invention, other vasodilating agents or preparations can also be used, e.g., dipyridamoleand sustainedaction preparations of nitroglycerine, isosorbide dinitrate and pentaerythritol tetranitrate. However, the use of these weaker agents does not provide the maximum degree of relief obtainable with the stronger agents such as isosorbide dinitrate. The chemical name of isosorbide dinitrate is l,4,3,6-dianhydrosorbitol-2,5- dinitrate. The chemical name of dipyridamole is 2,6- bis (diethanolamine)-4,8-dipiperidinopyrimido-(5,4- d)-pyrimidine.

The principal beta adrenergic receptor blocking agents for use in the compositions and method of this invention are l-(3,4-dichlorophenyl)-2- isopropylamino- 1 -ethanol, l-( 3,4-dihydrophenyI-2- isopropylamino-l-ethanol, l-(2,5-dimethoxyphenyl)- 2-methyl-2-t-butylamino- 1 -ethanol, l-( 3 ,4- dichlorophenyl )-2-methyl-2-isopropylaminol ethanol, l 4-methanesulphonylaminophenyl )-2- isopropylamino- 1 -ethanol, 1-( 3-tolyloxy)-3- isopropylamino-2-propanol, l-( 5 ,6,7,8- tetrahydronaphth-Z-yl )-2-s-butylamino- 1 -ethanol, 1 (2-allylphenoxy )-3-isopropylamino-2-propanol, l-( pnitrophenyl )-2-isopropylamino- 1 -ethanol, l-( pnitrophenyl )-2-n-butylaminoethanol and l- (isopropylamino)-3-( l-naphthyloxy )-2-propanol hydrochloride.

In the treatment of angina pectoris the vasodilating agent and the beta blocking agent can be administered together as a single composition or they can be administered separately either simultaneously or at relatively short intervals such that the therapeutic actions of the two drugs overlap. The time interval between the administration of each agent and the onset of therapeutic action as well as the duration of therapeutic action must be considered and these vary according to the particular agent used and the method of administration.

Normally, sublingual isosorbide dinitrate has an onset of action within five minutes and a duration of effect of approximately two hours but when taken orally onset of action is delayed more than 30 minutes and its duration of effect is about 1V2 hours. Sustained action preparations of the same drug have an onset within one half hour and a duration of up to eight or more hours. Oral pentaerythritol tetranitrate on the other hand has an onset of action in approximately one hour and a duration of effect up to four hours. Sustained action preparations of this drug may act for 8 hours or more. Oral propranolol hydrochloride, i.e., l-(isopropylamino)- 3( l-naphthyloxy)-2-propanol hydrochloride has an onset of action within 20 to 30 minutes and a duration of effect of 4 to 6 hours or more. The therapeutic effects of the two agents, when administered simultaneously, either separately or as a mixture, can be made to coincide more closely by the use of delayed action coating compositions on one or both of them to alter the normal interval before onset of action.

The amount of each drug used varies according to the particular combination of drugs and the method of administration; it also varies with the individual patient who should be titrated to determine the amount of each drug necessary for optimum pharmacologic response when administered alone. The dosage of each agent, determined in this manner is then used in the combinationsof my invention.

Typical single dosage ranges are as follows:

propranolol hydrochloride 10-120 (oral) lsosorbide dinitrate ZVz-IO (sublingual) isosorbide dinitrate 10-20 (oral) lsosorbide dinitrate 40-80 (sustained action) Pentaerythritol tetranitrate -40 (oral) Pentaerythritol tetranitrate 80 (sustained action) Erythrityl tetranitrate 5-15 (sublingual) Often the full recommended standard dosage of each drug can beadhered to without adverse effects when using my combination and l have also found that lesser dosages can sometimes be employed to provide excellent results. The fact that full dosages of each agent can be used is surprising since the use of an excess of either drug alone usually causes faintness or other adverse reaction. However, the results that l have obtained through the use of the two agents show more than a mere addition of the two beneficial effects produced by the separate operation of each drug. The results which I have observed demonstrate that a new and novel effect is produced by the combined action of a vasodilating agent and a beta blocking agent.

There is, moreover, inherent in the administration of beta blocking agents to patients, a danger that the subsidiary actions of the beta adrenergic blocking agents can gravely effect the patient. More particularly, the beta blocking agents have shown a tendency to constrict the coronary arteries, an effect which in some severely diseased patients can cause coronary insufficiency, heart failure, and even death. At best, such adverse subsidiary effects partially negate the favorable action of this class of drugs in decreasing the work and oxygen requirements of the heart. By the simultaneous administration of vasodilators with the beta blocking agents, this inherent danger is minimized and even eliminated because the primary effect of the vasodilabination of my invention can be further combined with a third agent, such as a sedative or tranquilizer, which acts upon non-coronary disorders or irregularities which are likely to precipitate an angina] attack.

EXAMPLES In order to demonstrate the utility of the compositions and method of my invention the following Examples are offered.

EXAMPLE 1 A year old male patient with a known history of severe angina pectoris and with a limited ability to walk more than 2 or 3 level blocks without pain was found, 1 hour after administration of a placebo, to demonstrate marked abnormal changes in his post-exercise electrocardiogram following a standard test consisting of 26 trips over a two-step staircase under controlled conditions. When an identical test was performed 1 hour following administration of 5 milligrams of isosorbide dinitrate, sublingual, the electrocardiographic patterns showed relatively slight improvements and this was also true of a test performed 2 hours after administration of 40 milligrams of oral propranolol hydrochloride. In each instance the test procedure was identical to that following administration of the placebo and the same number of trips were made by the patient, i.e., 26 trips. However, when the same test was performed 1 hour after the administration of 5 milligrams of isosorbide dinitrate, sublingual, and 2 hours after the administration of 40 milligrams of oral propranolol hydrochloride, i.e., during the effective period of the two drugs, a remarkable and unexpected improvement of the post-exercise electrocardiogram was observed and no abnormal response appeared. In other words, the response was that which would occur in a subject without disease. Moreover, the response recorded with each drug individually even with a summation of effects did not suggest the results observed after administration of the two drug combination.

EXAMPLE 2 The test procedure outlined above in Example 1 was repeated on the same patient using half dosages of each drug with the patient performing the same exercise, 26 trips over the two-step staircase. Two hours after administration of 20 milligrams (one-half of normal dosage) of oral propranolol hydrochloride the improvement in the post-exercise electrocardiogram over that observed after administration of the placebo was slightly less than the improvement observed after administration of 40 milligrams of the same drug. Similarly, when the 26-trip test was conducted 1 hour after administration of 2.5 milligrams (one-half of normal dosage) of isosorbide dinitrate, sublingual, the improvement in the post-exercise electrocardiogram was somewhat less than that observed with the full 5 milligram dose. However, when the identical test was conducted 2 hours after the administration of 20 milligrams of oral propranolol hydrochloride and 1 hour after the administration of 2.5 milligrams of isosorbide dinitrate sublingual (one-half dose) no abnormal responses in the post-exercise electrocardiogram were observed.

EXAMPLE 3 EXAMPLE 4 The test procedure of Example 1 was repeated on a second patient, a 60 year old male, with severe angina pectoris with the single exceptiomthat all testing was done 2 hours after administration of the drug or placebo and when the beta blocking agent and vasodilatpost-exercise electrocardiogram, 2 hours after placebo, showed markedly abnormal responses. Moderate improvement was observed minutes after administration of 5 milligrams of isosorbide dinitrate, sublingual,

and moderate improvement was also observed 2 hours after administration of 40 milligrams of oral propranolol hydrochloride. However, the post-exercise electrocardiogram 15 minutes after administration of 5 milligrams of isosorbide dinitrate, sublinguaLand 2 hours after administration of 40 milligrams of oral propranolol hydrochloride showed no abnormal response.

EXAMPLE 7 The four patients tested according to Example 1 through 6 above were subjected to exercise tolerance tests following administration of placebo; isosorbide dinitrate, 5 milligrams sublingual; propranolol hydrochloride, 40 milligrams oral, and isosorbide dinitrate, 5 milligrams sublinqual, plus propronolol hydrochloride, 40 milligrams oral. The results are shown in Table l below as the number of trips over the standard two-step staircase prior to the onset of pain or other indication of an anginal episode.

TABLE 1 Exercise Tolerance Trips Over Standard Two-Step Staircase Patient Age Placebo isosorbide Oral lsosorbide Dinitrate Sublingual Dinitrate Propranolol Plus Sublingual Hydrochloride Oral Propranolol Hydrochloride ing agent were both administered they were administered simultaneously; 30-trip tests were used. Again, markedly abnormal changes in the post-exercise electrocardiogram were observed following placebo, slight improvement was shown following administration of either drug alone and normal response occurred following administration of both drugs.

EXAMPLE 5 The test procedure of Example 1 was repeated on a third patient, a 77 year old female, with a known history of severe angina pectoris. All tests were conducted after 8 trips over the two-step staircase. Similar results were observed, namely, the post-exercise electrocardiogram, 2 hours after placebo, showed markedly abnormal responses. Moderate improvement was observed 15 minutes after administration of 5 milligrams of isosorbide dinitrate sublingual and moderate improvement was also observed 2 hours after administration of 40 miligrams of oral propranolol hydrochloride. However, 2 hours after administration of 40 milligrams of oral propranolol hydrochloride and 15 minutes after administration of 5 milligrams of isosorbide dinitrate, sublingual, the post-exercise electrocardiogram showed very slight abnormal responses, a major improvement over the results observed following administration of either drug alone.

EXAMPLE 6 The test procedure of Example 1 was repeated using 40-trip tests on a fourth patient, a 78 year old male, with a known history of severe angina pectoris. The

EXAMPLE 8 A 71 year old male with a history of angina pectoris of 10 years duration, complained of severe angina of effort on slight exertion. The attacks occurred on occasion even at rest. His electrocardiogram showed evidence of an old anterior myocardial infarction. Two years previously, he underwent surgery for the implantation of new blood vessels into his heart. This operation was followed by little success. When given placebo, the patient was able to ascend and descend a twostep staircase 26 times before the onset of pain. Fifteen minutes following the administration of erythrityl tetranitrate, 15 mg. sublingually, pain did not develop until 30 trips were performed. With a 40 mg. dose of propranolol hydrochloride administered one hour prior'to exercise, pain did not develop until 32 trips were performed on the two-step staircase. Following the administration of erythrityl tetranitrate and propranolol hydrochloride simultaneously, this patient was able to perform 46 trips on the two-step staircase prior to the development of typical chest pain. Electrocardiographic tests obtained with standard exercise employing the drugs in the order outlined above showed an ST-segment depression of 2.0 mm. with placebo, 1.2 mm. with erythrityl tetranitrate, 1.0 mm. with propranolol hydrochloride and no depression of the ST- segment with erythrityl tetranitrate and propranolol hydrochloride (a normal response). Pain was diminished by either erythrityl tetranitrate or propranolol hydrochloride alone, but was completely prevented when both drugs were administered prior to testing.

EXAMPLE 9 A 53 year old male with angina pectoris of l 1 years duration, sustained a myocardial infarction prior to the onset of angina. His attacks were brought on by slight exertion and occasionally even at rest and his electrocardiogram revealed evidence of coronary insufficiency. Following the administration of placebo, the patient experienced pain after ascending and descending the two-step staircase 16 times. One hour after the administration of erythrityl tetranitrate, mg. sublingually, pain did not arise until 20 trips were completed. The same pain arose after 22 trips following the prior administration of 40 mg. of propranolol hydrochloride, one hour before the test. When erythrityl tetranitrate and propranolol hydrochloride were administered, the patient performed 42 trips on the two-step staircase prior to the development of typical chest pain. Following standard exercise-electrocardiographic tests, the patient showed an ST-segment depression of 3.5 mm. with placebo, 3.0 mm. with erythrityl tetranitrate, 2.5 mm. with propranolol hydrochloride and 1.5 mm. with erythrityl tetranitrate and propranolol hydrochloride. Pain was diminished by either erythrityl tetranitrate or propranolol hydrochloride alone, but was completely prevented when both drugs were administered prior to testing.

The following are specific examples of formulations which can be used to manufacture 1,000 tablets according to my invention:

I claim:

1. The method of treating a patient suffering from angina pectoris by administering to the patient sublingually 2.5 to 10 mgs. of isosorbide dinitrate and per os 20 to 40 mgs. of l-(isopropylamino)-3-( l-naphthyloxy)-2- propanol hydrochloride. 

